Abscopal effect of radiotherapy and hyperthermia: role of exosomes

The review presents data on the role of ionizing radiation/hyperthermia as modulating factors in exosome secretion/composition. Tumor-derived exosomes are important participants in the formation of the tumor microenvironment. They modulate the inflammatory response in the tumor, influence the capability of fibroblasts and mesenchymal cells to differentiate into myofibroblasts, trigger the angiogenic process, promote epithelial to mesenchymal transformation of tumor cells and form the pre-metastatic nisches. The review describes the mechanisms of behavior of the recipient tumor cells receiving exosomes from irradiated cells, including activation of Akt signaling, stabilization of MMP9/MMP2, and enhancement of exosome-mediated motility. In vitro models demonstrate the efficacy of exosomes from mesenchymal stem cells (MSC) to modulate both direct and abscopal effects of radiation therapy/hyperthermia. Exosomes derived from MSC are the most attractive carriers for the delivery of proteins, miRNAs, drugs, and metals to the recipient tumor cells. MSC-derived exosomes potentiate the efficacy of both radiotherapy and hyperthermia in vitro studies. However, some important aspects regarding a) the most effective options for administering MSC/MSC exosomes to modulate radiotherapy/hyperthermia; b) radiation dose; c) options of hyperthermia; d) detailed mechanisms of the effect of irradiated MSC-derived exosomes on the tumor microenvironment and cancer cells, still remain poorly understood.